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oai:docta.ucm.es:20.500.14352/1061062025-03-18T13:17:26Zcom_20.500.14352_14col_20.500.14352_15

00925njm 22002777a 4500 dc Gárate, Iciar author García Bueno, Borja author Muñoz Madrigal, José Luis author Caso Fernández, Javier Rubén author Alou Cervera, Luis author Gómez-Lus Centelles, María Luisa author Leza Cerro, Juan Carlos author 2014-01-11 Background The innate immune response is the first line of defence against invading microorganisms and it is also activated in different neurologic/neurodegenerative pathological scenarios. As a result, the family of the innate immune toll-like receptors (TLRs) and, in particular, the genetic/pharmacological manipulation of the TLR-4 signalling pathway emerges as a potential therapeutic strategy. Growing evidence relates stress exposure with altered immune responses, but the precise role of TLR-4 remains partly unknown. Methods The present study aimed to elucidate whether the elements of the TLR-4 signalling pathway are activated after acute stress exposure in rat brain frontal cortex and its role in the regulation of the stress-induced neuroinflammatory response, by means of its pharmacological modulation with the intravenous administration of the TLR-4 specific inhibitor TAK-242. Considering that TLR-4 responds predominantly to lipopolysaccharide from gram-negative bacteria, we checked whether increased intestinal permeability and a resultant bacterial translocation is a potential regulatory mechanism of stress-induced TLR-4 activation. Results Acute restraint stress exposure upregulates TLR-4 expression both at the mRNA and protein level. Stress-induced TLR-4 upregulation is prevented by the protocol of antibiotic intestinal decontamination made to reduce indigenous gastrointestinal microflora, suggesting a role for bacterial translocation on TLR-4 signalling pathway activation. TAK-242 pre-stress administration prevents the accumulation of potentially deleterious inflammatory and oxidative/nitrosative mediators in the brain frontal cortex of rats. Conclusions The use of TAK-242 or other TLR-4 signalling pathway inhibitory compounds could be considered as a potential therapeutic adjuvant strategy to constrain the inflammatory process taking place after stress exposure and in stress-related neuropsychiatric diseases. Gárate I, García-Bueno B, Madrigal JL, Caso JR, Alou L, Gómez-Lus ML, Leza JC. Toll-like 4 receptor inhibitor TAK-242 decreases neuroinflammation in rat brain frontal cortex after stress. J Neuroinflammation. 2014 Jan 11;11:8. 1742-2094 10.1186/1742-2094-11-8 https://hdl.handle.net/20.500.14352/106106 https://doi.org/10.1186/1742-2094-11-8 https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-11-8 Toll-like 4 receptor inhibitor TAK-242 decreases neuroinflammation in rat brain frontal cortex after stress